In the past year, we have continued to make progress in assessing changes in thalamo-cortical relationships in the rodent model of Parkinsons disease. Both bradykinetic and dyskinetic states have been shown to be associated with dramatic increases in oscillatory and synchronized activity in the motor cortex. Current results support the idea that these changes in motor cortex LFP activity are driven by alterations in the activity of thalamic input to cortex. However, our data to date does not support the view that the increases in LFP oscillations in the motor cortex are necessarily causing the motor symptoms. The emergence of dyskinesia in this animal model of Parkinsons disease can be disassociated from increases in high gamma range LFP activity in the motor thalamus and motor cortex. The role of the high beta/ low gamma oscillatory activity observed in the ventromedial thalamocortical projection during periods of bradykinesia in these animals is still under debate. While we are unsure of the actual consequences of the high beta/low LFP oscillations in the motor cortex, the thalamic component of the basal ganglia- thalamo-cortical loop does seem critical to the emergence of these LFP oscillations after loss of dopamine. We are working on the near-final draft of a manuscript reporting data from recordings of spike/local field potential (LFP) relationships between basal ganglia output, substantia nigra pars reticulata (SNpr), motor thalamus and motor cortex in hemiparkinsonian rats trained to walk on a circular treadmill. These recordings of LFP activity from multiple sites within the motor network show correlated increases in coherence between motor cortex and SNpr, between motor cortex and ventral medial thalamus, and between SNpr and ventral medial thalamus in the 30-35 Hz range after dopamine cell lesion during treadmill walking. Infusion of the GABA agonist muscimol into the ventral medial nucleus to inhibit activity in this nucleus causes a reduction of power in both motor cortex and SNpr LFP and reduced coherence between these two sites in the high beta/low gamma range during treadmill walking. We cannot draw conclusions from the behavioral effects of this treatment on treadmill walking, however, as inhibiting the activity in this nucleus with muscimol infusion reduces walking in the circular treadmill in both the unilaterally lesioned rat and the normal rat. Some form of thalamocortical activity appears critical for normal treadmill walking. In contrast, the GABA antagonist, picrotoxin, infused into the ventral medial thalamus, mimics the impact of L-dopa on treadmill walking. Presumably, by blocking the oscillatory inhibitory input from the SNpr to the ventral medial thalamus, this drug reduces beta range activity in the ventral medial thalamus, and facilitates treadmill walking. This data supports a role for the ventral medial thalamus in maintenance of normal motor function and is consistent with a role for the motor thalamus in induction of high beta/low gamma synchronization of LFP activity in the motor cortex. The data also shows that neuronal activity in the ventral medial thalamus promotes increased coherence within the larger basal ganglia thalamo-cortical network after loss of dopamine. Future experiments will attempt to gain insight into the relationship between these oscillations in the cortex and the dysfunction evident during treadmill walking in the direction contraversive to the unilateral dopamine cell lesion. We are currently developing new electrodes to allow us to record locally as we infuse test drugs and as we apply optogenetic techniques to modify spiking activity to more selectively probe the different nodes of this circuit, and the manner in which thalamocortical activity ultimately impacts downstream systems regulating limb movement. We have also made progress on a series of studies examining the changes in thalamic and thalamo-cortical activity associated with chronic treatment of L-dopa. The therapeutic effect of treatment of Parkinsons disease patients with the dopamine precursor L-dopa has been well established. However, over time, L-dopa therapy leads to severe motor complications referred as L-dopa-induced dyskinesias (LID). Recently, we have confirmed that there is a strong association between the presence of 80-100 Hz high gamma oscillations in the motor cortex of hemiparkinsonian rats and LID expression. This is especially interesting because high gamma has been observed in human PD patients in recordings through deep brain stimulation electrodes, and the role of this activity in generating dyskinesia is unclear. This activity has been referred to in the clinical literature as finely tuned gamma or FTG . As with the high beta/low gamma activity in the 30 36 hz range, our studies have shown that the motor thalamus is critical for the emergence of the 80-100 Hz activity evident in the motor cortex during LID in the hemiparkinsonian rat after priming with L-dopa. We are also examining the time course and correlations between the LID and the changes in cortical activity. A number of results show that dyskinetic behaviors and FTG emerge together. For example, pre-treatment with amantadine, a weak NMDA glutamate receptor antagonist used clinically to treat dyskinesia, mildly reduced both 100 Hz LFP power and LID. A manuscript is in final stages reporting this data. Other results show the FTG and the dyskinetic behavior can be disassociated. While a 0.3 mg/kg dose of MK-801, the NMDA GluR antagonist, eliminated both FTG and dyskinesia, a lower 0.15 mg/kg dose of the MK-801 administered i.p. abolished 100 Hz band oscillations without affecting LID. Results show that suppression of ventromedial thalamic activity by local injection of the GABA receptor agonist muscimol completely eliminated aberrant 100 Hz synchronization within the motor cortex, but had nearly no effect on LID. The results suggest that while robust high gamma oscillatory activity in both motor thalamus and motor cortex is evident during LID, this aberrant thalamocortical synchronization does not appear to be requisite for the expression of dyskinesia. Most recently, we have focused on the role of the motor thalamus in inducing the cortical FTG. We are also exploring the possible role of the cerebellum in contributing to the dramatic changes in thalamocortical activity observed in this model of L-dopa induced dyskinesia. Further evidence that the motor thalamus is driving the FTG in the cortex emerges from studies of rate and spike-LFP phase-locking in the motor thalamus during LID. Treatments that induce or block the availability of L-dopa modulate the high gamma LFP activity in both motor thalamus and motor cortex, and allow us to track how activity in the two areas changes with changes in LFP . Interestingly, changes in firing rate and phase-locking are highly correlated with the changes in power in the high gamma range in the ventromedial thalamus, but not in the motor cortex. It appears that power in this high gamma range can change dramatically in the motor cortex LFP without an associated changes in spike-LFP phase locking. Firing rate changes are not obvious either, in our analysis to date. More remains to be done, but studies to date raise interesting questions about the consequences of the high gamma range activity in the motor cortex. Gamma activity is generally considered an important modulator of cortical function, and we are hopeful that insight into the causes and consequences of expression of exaggerated levels of this activity, as occurs following chronic L-dopa treatment after loss of dopamine, will provide insight into both normal and pathological roles of this activity